It is known that calcium ions (Ca.sup.++) play vital roles in many cell processes. Calcium ions are particularly important to the function of cardiac tissue and vascular smooth muscle. The transition from the resting to the active state in the myocardium is initiated by cell depolarization which may be recorded as transmembrane action potential comprising a sharp peak caused by movement of sodium ions into the cell followed by a prolonged plateau during which calcium ions move into the cell. When intracellular concentrations of calcium ions rise above 10.sup.-7 M, contraction occurs. The elevation of calcium ion concentration is believed to remove the inhibitory influence of the troponin-tropomyosin complex on the actin and the myosin necessary for contraction.
The movement of sodium and calcium ions into the cells is considered to be through "channels" in the cell membrane. The extent of influx of calcium ions appears to be dependent on the number of channels open and the extent of their opening. The extent of opening appears to be dependent on membrane depolarization, phosphorylation of certain protein kinases and activation of specific membrane receptors. The channels may be blocked by certain chemical compounds.
In view of the central role played by calcium ions in the electrophysiological and mechanical properties of the heart, and in the systemic and coronary arteries, the blocking of calcium ion channels can produce alterations in cardiovascular functions which can be advantageously employed in the treatment of a wide variety of cardiac disorders including cardiac arrhythmias, angina pectoris, arterial hypertension, hypertrophic obstructive cardiomyopathy and the like.
The effect of chemical compounds on the role played by calcium ions in cardiovascular functions is still being studied and suitable drugs are still being sought. Compounds which have been reported to be active as calcium entry blockers represent different types of chemical compounds. Thus, some of the drug names and their chemical names are as follows: Nifedipine, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester; Verapamil, .alpha.-[3-[2-(3,4-dimethoxyphenyl)-ethyl][methylamino]propyl]-3,4-dimetho xy-.alpha.-(1-methylethyl)benzeneacetonitrile; Prenylamine, N-(1-methyl-2-phenylethyl)-.alpha.-phenylbenzenepropanamine; Perhexiline, 2-(2,2-dicyclohexylethyl)-piperidine; Diltiazem, 3-(acetyloxy)-5-[2-(dimethylamino)-2,3-dihydro-2-(4-methoxyphenyl-1,5-benz othiazepin-4-(5H)-one; Cyproheptadine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine, and others.
Representative literature disclosing the foregoing compounds in calcium entry blocker activity include: D. A. Lowe et al., Br. J. Pharmacol. (1981) 74, 651; P. D. Henry, Am. J. Cardiology, 48, 1047 (1980); L. D. Hillis, J. Cardiovasc. Med. 5(6), 583, (1980); and R. A. Janis et al., J. Med. Chem. 26(6), 775 (1983).
A number of piperazines which are substituted on one nitrogen with a dibenzo[a,d]cycloalkenyl or analogous group, and on the other nitrogen with alkyl, cinnamyl, cinnamoyl, or carbalkoxy group have been reported to have pharmacological properties. The properties possessed by certain of the compounds are vesicatory (U.S. Pat. No. 3,357,982), psychostimulant (U.S. Pat. No. 4,144,337), antidepressant (British No. 1,127,354 and J. Med. Chem. 22, 183 (1979)) and antiulcer (British No. 1,029,920). None of these piperazine compounds are reported to have properties as calcium entry blockers.